Activity of Antifungal Organobismuth(III) Compounds Derived from Alkyl Aryl Ketones against S. cerevisiae: Comparison with a Heterocyclic Bismuth Scaffold Consisting of a Diphenyl Sulfone

A series of hypervalent organobismuth(III) compounds derived from alkyl aryl ketones [XBi(5-R'C(6)H(3)-2-COR)(Ar)] was synthesized to investigate the effect of the compounds’ structural features on their antifungal activity against the yeast Saccharomyces cerevisiae. In contrast to bismuth heterocycles [XBi(5-RC(6)H(3)-2-SO(2)C(6)H(4)-1'-)] derived from diphenyl sulfones, a systematic quantitative structure-activity relationship study was possible. The activity depended on the Ar group and increased for heavier X atoms, whereas lengthening the alkyl chain (R) or introducing a substituent (R') reduced the activity. IBi(C(6)H(4)-2-COCH(3))(4-FC(6)H(4)) was the most active. Its activity was superior to that of the related acyclic analogues ClBi[C(6)H(4)-2-CH(2)N(CH(3))(2)](Ar) and ClBi(C(6)H(4)-2-SO(2) tert-Bu)(Ar) and also comparable to that of heterocyclic ClBi(C(6)H(4)-2-SO(2)C(6)H(4)-1'-), which was the most active compound in our previous studies. Density function theory calculations suggested that hypervalent bismuthanes undergo nucleophilic addition with a biomolecule at the bismuth atom to give an intermediate ate complex. For higher antifungal activity, adjusting the lipophilicity-hydrophilicity balance, modeling the three-dimensional molecular structure around the bismuth atom, and stabilizing the ate complex appear to be more important than tuning the Lewis acidity at the bismuth atom.